1. Field of the Invention
The present invention generally relates to photodynamic therapy for wound healing and cosmetic application, particularly to methods and compositions that will enhance the healing process of injured epidermal and connective tissue wounds, thus promoting tissue reconstruction and augmentation.
2. Information Disclosure Statement
A wound is a disruption of skin tissue integrity causing loss of function in the region. A wound can be simple like minor cuts or abrasion involving the epidermal and superficial dermal layers and is termed as partial-thickness wound. This heals faster by re-epithelialiazation; while complicated/full thickness wounds are deeper injuries to the skeletal system, the muscle tissue or even to the inner organs. Wounds can be a traumatic wound like abrasion, contusion, laceration; or a surgical wound-skin graft, post-surgical incisions which are easiest to heal; or its can be chronic/non-healing wound like pressure sores, or diabetic ulcers which are more difficult to heal. Injuries to connective tissue like bone, cartilage are also very common. Finally burn injuries especially of the second and third degree, where tissue loss results in scarring and disfigurement and delays the healing process, are also a major concern.
Wound healing is a dynamic process involving physiological, biochemical and morphological alterations. The process of repair and reconstruction following injury is one of the most fundamental defense mechanisms against environment. This healing process consists of an orderly progression of events that reestablish the integrity of the damaged tissue. It comprises separate yet overlapping phases namely—hemostasis, inflammation, proliferation, angiogenesis and remodeling by accumulation of matrix and necessary cells to heal the injured part. All healthy living organisms have an innate ability to heal the wounds. But in certain cases wounds may not heal easily or there is a delay due to impaired immunity, poor health conditions, and/or poor nutrition; for example in diabetic patients wound healing is impaired and even a simple cut can manifest into a chronic wound if immediate medical care is not provided. New technologies are being developed to improve the healing in these conditions.
Wound healing is a complex process involving a variety of different cells, proteins, chemo-attractants, proteinases, inflammatory cells, cytokines and growth factors. Healing process is regulated by growth factors and cytokines that affect cell migration, proliferation and protein production. Immediately after injury, the wound fills with blood and a clot is formed to stop bleeding. If tissues are damaged, a cascade of cellular events is initiated to prepare the injured area for the deposition of collagen, which ultimately will replace damaged tissues. During inflammatory phase the bleeding is controlled and immune system is activated to control the bacterial infection; and granulation tissues are formed during the proliferative phase which covers the injured area. This is followed by angiogenesis and remodeling.
Understanding the function of cytokines, growth factors, and other mediators involved in wound healing process can help us manipulate these component to heal the wound faster thus improving function and aesthetics. Conventional methods of local wound treatment which is most widely practiced consists of mechanical cleaning, disinfection with antiseptic solutions, wound debridement, wound closure, antibiotic treatments, and wound closure by surgical methods.
Wound healing is controlled via a combination of three mechanisms: contraction, epithelialization, and connective tissue deposition. Wound-type (i.e. abrasions, lacerations, etc.) will determine which of these three mechanisms will emerge as the predominate mechanism in the healing process. For example, the healing of abrasions is predominated by epithelialization, whereas for sutured lacerations the principle mechanism is connective tissue deposition. Closing wounds by surgical methods remains the best way of promoting wound healing, however, not all wounds are suited for surgical intervention. Anatomical location as well as the surface area and/or depth of a wound can make surgical methods of wound closure impossible or impractical. Moreover, the tissue removal and scarring that follows some surgical methods can be highly disfiguring and debilitating. Extensive wounds, such as burns, restrict limb movement or function as a result of skin contractures due to the shrinking of scar tissue in the skin or connective tissues at the wound site.
Latest treatment method is use of tissue engineered ‘skin substitutes’. Wherein scientist have developed grafts using sheet of fibroblasts embedded in biodegradable matrix, sheet of cultured kerationcytes and dual layered dermal/epidermal engineered skin. One such example is use of Integra artificial skin (developed by Burke and Yannas in 1980s). Yannas at al in his U.S. Pat. No. 4,947,840 disclose the use of this biodegradable artificial skin implant for delaying the contraction and promoting tissue regeneration in burn wounds with tissue loss. Integra DRT can only replace deeper skin layer of deimis and still require a skin graft to cover it and prevent from infection.
Many such products have been approved by FDA (examples: Integra DRT, TransCyte). Integra Dermal Regeneration Template (DRT) is a cell free matrices comprising of porous collagen/chondritein-6 sulphate matrix overlaid with thin silastic sheet. This template acts as a framework for dermal regeneration thus inhibiting scaring and promotes healing. Like cell-free matrix, cell-containing matrices are also used for grating; examples are Dermagraft, Apligraf, and Hyalograft-3D (skin grafts comprised of semi-artificial dermis) etc. Even destruction of bone and cartilage tissue due to disease and inefficient bone healing after traumatic injury may be addressed by tissue engineering techniques. But tissue engineered skin grafts are expensive and timely for lager scale production. Some times this skin graft show poor take rate and often fails to graft onto the patients.
Recently, there has been considerable interest in the effects of light on wound healing. Certain lasers have proven to be an efficacious, noninvasive method of accelerating the healing process. For example, the use of high powered 980 nm lasers to accelerate wound healing was described by Neuberger in U.S. Pat. No. 6,165,205. Thus, laser assisted wound healing would make an attractive alternative to surgical methods. Photodynamic therapy (“PDT”) is another laser treatment method that uses specific wavelength irradiation to activate a photosensitizer drug. Photoactivation of the drug induces localized oxidative damage in the diseased tissues where the photosensitizer has preferentially accumulated. PDT is thought to have a positive effect on the wound healing process as well.
As the consequence of continual research in the field of wound healing it is found that light therapy can improve tissue healing. Low power laser energy has been used for wound healing as it can apparently elicit a cellular response thus promoting healing process. U.S. Pat. No. 6,165,205 by Neuberger discusses the use of high power non-ablative laser to accelerate wound healing. A 980 nm diode laser is employed here to activate fibroblast cells and collagen synthesis at the wound site to promote wound healing. While in U.S. Pat. No. 6,527,764 by the same inventor a device is described for laser treatment that combines activating laser power with biomodulation power to enhance tissue healing and regeneration after treatment.
In the last decade, low energy light source have been used to treat wounds or lesions in a variety of tissues. Low level lasers especially He—Ne lasers have been found to promote epithelization in full thickness wounds. In fact NASA has developed a handheld LED which greatly enhances wound healing and musculoskeletal injuries. LED and Low Level Laser therapy have been found to increase fibroblast proliferation in vitro (Vinck et al). Studies using low power light sources from visible, near infrared or near ultraviolet (UVA) light have been shown to be effective in promoting cell proliferation and growth while a high energy light can inhibit cell growth.
For example, a PDT method for modulating the healing process in unhealed or partially healed wounds has been described by Trauner et al. in U.S. Pat. No. 5,913,884. Trauner et al. disclose and claim a high dose PDT method for inhibiting fibrosis, the rapid production of dense bands of collagen during the healing process. Trauner describes a three step process involving light irradiation of the wound site after the administration of a photosensitizer conjugated to a targeting moiety that is specific for macrophages or myofibroblasts.
Hasan et al. disclose a low dose PDT method for accelerating wound healing in U.S. Pat. No. 6,107,466. Hasan's PDT method requires a three step process involving light irradiation of the wound site after the administration of a photosensitizer and is purported to stimulate the secretion of growth factors in cells at a wound site. Moreover, Hasan et al. claim a PDT method that accelerates wound healing without causing tissue destruction.
PDT is a new treatment modality used for treating certain type of cancers, however the use of PDT in healing and scar removal is under intense research but not fully explored. Resistant bacterial growth in the wound site needs to be controlled to promote healing. Ultraviolet light (UVA) have been reported to kills this bacterial cells. While in PDT treatment methods, the PS may be tagged to target specifically bacterial cells so that photoactivation reaction will destroy the bacterial cells.
Use of PDT in wound healing process has been reported in U.S. Pat. Nos. 6,107,466 and 5,913,884 by Hasan et al and Trauner et al respectively. U.S. Pat. No. 6,107,466 describes a PDT treatment method for accelerating healing process in unhealed and partially healed wounds. In this patent an effective dose of PDT is selected to stimulate production of growth factors without damaging the cells to promote healing at the wound site. Trauner et al. in their patent (U.S. Pat. No. 5,913,884) describe a three step PDT method to treat unhealed and partially healed wounds by either inhibiting fibrosis by using high dose PDT or hastening the healing process by low dose PDT.
While these references discuss PDT in connection with wound healing, none of them describe or disclose how or why a PDT method, for cases where tissue augmentation or replacement is a key factor with attendant wound healing, would be beneficial or could be used. Beyond that there are many examples where for ‘wound-free’, healthy tissue there are times where enhancement of the ‘healthy tissue’ by tissue augmentation or replacement is particularly desired.
Accordingly, there is an urgent need for a reliable and practical method of tissue repair and wound closure that is appropriate for full or partial thickness wounds such as burns or chronic ulcerations. For wounds where tissue augmentation or replacement is necessary a non-surgical treatment method that promotes or accelerates the healing process while minimizing scarring and the risk of infection is highly desirable. The present invention addresses this need.
The present invention, aims at overcoming the above discussed drawbacks of currently used treatment procedures for healing complicated wounds. This invention provides minimally invasive non-surgical PDT based treatment method that promotes wound healing and minimizes scarring. Furthermore this invention is not only for all types of partial and full thickness wounds, but also to reduce scars, wrinkles and other skin imperfection or cosmetic conditions.